1. Field of the Invention
The present invention relates to the field of dissolution testing and, in particular, to apparatuses for intrinsic dissolution testing of pharmaceuticals in solid, semi-solid, and transdermal dosage form.
2. Description of the Related Art
In general, dissolution testing is used to determine the rate of dissolution of a material in a solvent or solution. For example, dissolution testing may be used to determine the rate of dissolution of pharmaceuticals in dosage form in specific dissolution mediums to simulate digestion in a human. The requirements for such dissolution testing apparatuses are provided in United States Pharmacopeia (USP), Edition XXII, Section 711, Dissolution (1990).
Conventional dissolution testing apparatuses have one or more dissolution vessels in which dissolution media may be placed. One conventional configuration of a dissolution testing apparatus has, for each dissolution vessel, a paddle-type stirring element consisting of a metal shaft with a metal blade at the end. After placing the dosage to be dissolved loose at the bottom of the vessel, the stirring element is lowered into the dissolution medium near the center of the vessel and rotated at a specified rate (typically measured in revolutions per minute (rpm)) for a specified duration. Samples of the dissolution media may be periodically withdrawn from the vessels to determine the degree of dissolution of the dosages as a function of time.
One of the problems with this conventional configuration for dissolution testing is that the total exposed surface area of the test sample changes (i.e., decreases) over the testing cycle as the dosage is dissolved. Since the instantaneous dissolution rate is a function of the current total exposed surface area of the test sample, it is hard to correlate how dissolution rate varies as a function of time when the surface area also changes over the testing cycle. To address this problem, intrinsic dissolution testing may be performed.
The intrinsic dissolution rate is defined as the rate of dissolution of a pure pharmaceutical active when conditions such as the total exposed surface area of the sample as well as the temperature, agitation-stirring speed, pH, and ionic strength of the dissolution medium are kept constant. The determination of the intrinsic dissolution rate allows for screening of drug candidates and in understanding their solution behavior under different bio-physiological conditions.
The implementation of xe2x80x9csamenessxe2x80x9d analysis has been presented and applied in a number of scientific guidelines for demonstrating formulation equivalencies among semi-solids, immediate-release solid oral, and extended-release solid oral dosage forms. Conventional test methods for these analyses involve the use of vertical diffusion cells, enhancer cells, and the USP apparatuses 1 and 2. The evaluation of the intrinsic dissolution of active pharmaceutical ingredients (API) is a means to demonstrate chemical equivalency. The need to demonstrate xe2x80x9csamenessxe2x80x9d among APIs has risen due to changes in the bulk active synthesis, the final crystallization steps, particle size and surface area, polymorphism and scale-up issues regarding batch-size and manufacturing site.
Currently the USP lists the Wood""s Intrinsic Dissolution Apparatus from VanKel Industries, Inc., of Cary, N.C. as the official apparatus for determination of intrinsic dissolution rates. See USP 24-NF 19 Supplement 1, Section 1087, Intrinsic Dissolution (Released Nov. 1, 1999).
FIG. 1 shows a cross-sectional view of a prior-art intrinsic dissolution test configuration 100 based on the Wood""s Intrinsic Dissolution Apparatus. Test configuration 100 comprises a rotatable shaft 102 positioned over the center of a round-bottomed dissolution vessel 104. At the end of shaft 102 is a die 106 rigidly connected to shaft 102 by a die holder 108. A drug pellet (i.e., the test sample) is formed and retained within a cylindrical recess 110 centered on the bottom face 112 of die 106. After an appropriate dissolution medium (not shown) is placed within vessel 104, shaft 102 is lowered into the dissolution medium within vessel 104 to position the bottom of die 106 at a specified distance (e.g., 1 to 1.5 inches) above the bottom of the vessel. During intrinsic dissolution testing, shaft 102 is rotated, thereby rotating the drug pellet contained within recess 110. Dissolution is achieved by shear-like motion of the pellet within the dissolution medium. Since the drug pellet has the same shape as cylindrical recess 110, in theory, the total exposed surface area of the test sample should remain substantially constant during the dissolution testing cycle as the drug pellet dissolves.
FIG. 2 shows an exploded, cross-sectional view of conventional equipment used to form the drug pellet within cylindrical recess 110 of die 106 of FIG. 1. As shown in FIG. 2, die 106 is secured to a base plate 202 by a number of screw pins inserted through openings 204 in base plate 202 and screwed into corresponding tapped holes 206 on the bottom face 112 of die 106. Test sample material 207 in powder form is then placed within a cylindrical die cavity 208 within die 106, and pressure is applied with a plunger 210 to press the powdered material against base plate 202 to form a cylindrical drug pellet at the bottom of cavity 208. Retaining male end 212 of plunger 210 within cavity 208 forms cylindrical recess 110 of FIG. 1. Die holder 108 is then screwed onto threaded end 214 of die 106 with an intervening O ring or other gasket 216 that prevents the dissolution medium from reaching the drug pellet through the upper end of cavity 208. Base plate 202 may then be removed (by removing the screw pins) to provide the subassembly of die holder 108 and die 106 shown in FIG. 1 with a drug pellet formed and positioned within recess 110 of die 106, ready for intrinsic dissolution testing.
One of the problems with the conventional intrinsic dissolution test configuration of FIG. 1 relates to the formation of air bubbles at the exposed (i.e., bottom) surface of the test sample. Such air bubbles can interfere with dissolution testing by decreasing the effective dissolution rate. Air bubbles may come from different sources. First of all, air bubbles may be formed when the test sample is initially lowered from air into the dissolution medium. In addition, air bubbles may be formed as the test sample dissolves either from air trapped within the drug pellet or as a by-product of the dissolving of the sample material itself.
Another problem is that the shaft and die assembly of FIG. 1 may wobble when operated at high rotation speeds (e.g., 100 rpm). Such wobbling may alter the effective dissolution rate, thereby leading to further inaccuracies in the test results.
In addition, the temperature of the dissolution medium may change (e.g., drop about 2xc2x0 C.) when the relatively massive shaft and die assembly are first inserted into the dissolution medium, with heat being removed from the dissolution medium through the shaft.
The present invention is directed to a configuration for intrinsic dissolution testing that addresses these problems with the prior art. According to the present invention, a drug pellet is retained within a sample holder that is positioned at the bottom of the dissolution vessel with the drug pellet facing up. The dissolution medium may then be stirred, e.g., using a conventional rotating paddle positioned above the stationary sample holder.
Intrinsic dissolution testing equipment according to the present invention decreases the likelihood of air bubbles adversely affecting test results during the testing cycle. Moreover, since the sample holder is stationary during the testing cycle, any wobbling of the rotating paddle at high speeds will not directly affect the effective dissolution rate. In addition, since the sample holder is placed at the bottom of the vessel before dissolution testing begins, there is no significant temperature change to the dissolution medium when the relatively low-mass rotating paddle is lowered into the dissolution medium. Each of these factors may contribute to an improved ability of the present invention to achieve more accurate and consistent intrinsic dissolution test results.
In one embodiment, the present invention is a method for performing intrinsic dissolution testing, comprising the steps of (a) forming a test sample within a recess of a sample holder; (b) placing the sample holder within a dissolution vessel containing a dissolution medium with the sample holder oriented with the test sample facing up; and (c) performing intrinsic dissolution testing for the test sample with the sample holder substantially stationary within the dissolution vessel.
In another embodiment, the present invention is an apparatus for intrinsic dissolution testing, comprising (a) a die having a die cavity; (b) a plunger configured to be inserted within the die cavity to define a recess for retaining a test sample at a first side of the die; and (c) a cap configured to be secured over a second side of the die to form a sample holder, wherein the cap has a shape that conforms sufficiently to the shape of the bottom of a vessel used during the intrinsic dissolution testing to keep the sample holder substantially stationary at the bottom of the vessel with the test sample retained within the recess oriented facing up within a dissolution medium.